JPH04316531A - Cyclohexanone derivative - Google Patents

Abstract

PURPOSE: To provide a novel cyclohexanone deriv. useful as an intermediate for a cyclopentane deriv. having sterilizing activity.

CONSTITUTION: The compd. of formula I ((n) is an integer from 0 to 5; respective R are halogen, NO₂, CN., OH, alkyl, haloalkyl, alkoxy, haloalkoxy, NH₂, mono-dialkylamino, alkoxycarbonyl, COOH, alkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, CONH₂, alkylamide, cycloalkyl, phenyl, R¹ to R³ are H, alkyl; R⁶, R⁷ are, together, a single C-C bond or epoxy; R⁸ is H, OH, when R⁶ and R⁷ are epoxy, R⁸ is H); for example, 1-C4-chlorbenzyl)-4,4-dimethylcyclohexy-1- ene-3-one. The compd. in which R⁸ is H is obtd. by bringing the compd. of formula II into reaction with an oxidizing agent in the presence of an acid, then bringing the product into reaction with hydrogen peroxide in the presence of a base it desired.

COPYRIGHT: (C)1992,JPO

Description

[Detailed description of the invention]

The present invention relates to certain cyclohexanone derivatives that are useful as intermediates in the production of fungicidally active cyclopentane derivatives, and to processes for their production.

According to the invention, the general formula:

[Formula, n represents an integer of 0 to 5; each R is a halogen atom, nitro, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl,
represents an alkylamide, cycloalkyl or phenyl group; R1, R2 and R3 independently represent a hydrogen atom or an alkyl group; R6 and R7
together represent a single carbon-carbon bond or an epoxy group; R8 represents a hydrogen atom or a hydroxyl group; however, if R6 and R7 together represent an epoxy group, R8 represents a hydrogen atom] A compound is provided.

If any of the above substituents represents or contains an alkyl substituent, this can be straight-chain or branched and contains up to 12, preferably up to 6, especially 4
It can have up to 2 carbon atoms. Cycloalkyl substituents can have 3 to 8, preferably 3 to 6 carbon atoms. It is preferable that R1, R2 and R3 independently represent a hydrogen atom or a C1-4 alkyl group, particularly a methyl group. Preferably, R is halogen,
Specifically indicates a chlorine atom. A particularly preferred class of compounds of formula I is in which n is 1, R represents a chlorine atom (preferably substituted in the 4-position of the phenyl ring), and R1 and R2
Both represent a hydrogen atom or both represent a methyl group, and R3 represents a hydrogen atom or a methyl group.

The present invention further provides a method for preparing a compound of formula I above, which method comprises (a) the general formula:

[Image Omitted] A compound of [Formula n, R, R1, R2 and R3 have the above meanings] is reacted with an oxidizing agent to form R6
and R7 together represent a single carbon-carbon bond and R8 represents a hydrogen atom;

(b) If desired, the compound of formula I produced in step (a) is reacted with hydrogen peroxide in the presence of a base so that R6 and R7 together represent an epoxy group and producing a compound of formula I in which R8 represents a hydrogen atom;
(c) If desired, the compound of formula I produced in step (b) is dissolved in the presence of a polar solvent to the general formula: MOR5
(III) [wherein R5 is a hydrogen atom or alkyl, preferably C1-6 tertiary alkyl, especially C4-6
represents a tertiary alkyl or cycloalkyl group, preferably a C3-6 cycloalkyl group, and M represents an alkali metal, preferably a sodium or potassium atom]
to form compounds of formula I in which R6 and R7 together represent a single carbon-carbon bond and R8 represents a hydroxyl group.

Preferably, the oxidizing agent in step (a) is a chromium (VI) salt, such as an alkali metal dichromate, especially sodium or potassium dichromate. When using alkali metal dichromates as oxidizing agents, the reaction is preferably carried out in the presence of an acid. Furthermore, it is preferred that the acid is a dilute mineral acid, with dilute sulfuric acid being particularly preferred. Step (a) may conveniently be carried out in the presence of a solvent. Suitable solvents include ethers such as diethyl ether. Alternatively, the acid can act as a solvent. The reaction is suitably carried out at a temperature ranging from 0 to 70°C, preferably from 10 to 60°C.

Preferably, the base in step (b) is an inorganic base, such as sodium hydroxide, potassium hydroxide or quaternary ammonium hydroxide. Step (b) may conveniently be carried out in the presence of a solvent. Suitable solvents include alcohols such as methanol, ethanol and especially t-butanol. Preferably the reaction is -10 to 6
It is carried out at a temperature in the range of 0°C, preferably 0 to 50°C. Preferably, the polar solvent in step (c) is an alcohol, preferably a C1-6, especially a C4-6 tertiary alcohol. When alcohol is used as the solvent, it is preferred that the alkyl moiety in the alcohol is the same as R5 in the compound of formula III. For example, if the compound of formula III is potassium t-butoxide, the alcohol is preferably t-butanol. The reaction is conveniently carried out at a temperature ranging from 30°C to the reflux temperature of the solvent.

Compounds of formula II are conveniently of the formula:

[Image Omitted] A compound of [wherein R1, R2 and R3 have the above meanings] is represented by the general formula:

embedded image where R and n have the above meanings and L is an organometallic group, such as lithium or a group -MgHal (where H
al represents a chlorine or bromine atom)]. Compounds of formula II and methods for their preparation are described in patent application T689 by the applicant.
form the subject of. Compounds of formulas III, IV and V are known compounds or can be prepared by methods analogous to known methods.

Compounds of formula I have the general formula:

Useful as an intermediate in the production of bactericidal cyclopentane derivatives [wherein n, R, R1, R2 and R3 have the above meanings, and A represents a nitrogen atom or a CH group] It is. Certain compounds of formula VI are described in patent applications GB-A1-2180236 and EP
-A2-0267778. EP-A2-
The compounds disclosed in Nos. 0267778 and GB-A1-2180236 exist in two stereoisomeric forms and have the following structures:

0010

[Chemical formula 8]

[Chemical formula 9]

In the following, the symbols A and B are used to indicate compounds having the same stereochemical configuration as isomers A and B above. Isomers A and B can be separated, for example by chromatography, and exhibit different fungicidal activities. Generally, isomers of formula VIA exhibit greater fungicidal activity than isomers of formula VIB. The method used to synthesize compounds of formula VIA from compounds of formula I where R6 and R7 together represent a single carbon-carbon bond and R8 represents a hydroxyl group is illustrated in the following reaction scheme:

0012

[Chemical formula 10]

In the above reaction formula, n, R, R1, R2
, R3, R5, M and A have the above meanings,
R4 is an appropriately substituted alkyl or aryl group,
Preferably it represents a C1-4 alkyl or phenyl group, and if necessary, a halogen atom, nitro, cyano, hydroxyl, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1- 4 alkylamino, di-C1
-4 alkylamino, C1-4 alkoxycarbonyl, carboxyl, C1-4 alkanoyl, C1-4
Alkylthio, C1-4 alkylsulfinyl, C
1-4 alkylsulfonyl, carbamoyl, C1-4
substituted by one or more substituents selected from alkylamides, C3-8 cycloalkyl and phenyl groups, X represents a halogen, preferably a chlorine or bromine atom, and Q represents hydrogen or an alkali metal, preferably sodium Or indicates a potassium atom. The intermediate compounds and steps in the above reaction formula are described in patent application T693 and European patent application No. 89202 by the applicant.
No. 159.3 and UK Patent Application No. 8820607.3
This is the subject of the issue.

The present invention will be further explained below with reference to Examples. Example 1 Production of 1-(4-chlorobenzyl)-4,4-dimethylcyclohex-1-en-3-one (n=1, R=4-Cl, R1=R2=C
H3, R3 = H, R6 and R7 = single C-C bond, R8 = H) (a) Preparation of 1-(4-chlorobenzyl)-4,4-dimethylcyclohex-2-en-1-ol A solution of 4-chlorobenzyl chloride (266 g, 1.65 mol) in diethyl ether (200 ml) was dissolved in magnesium (42 g, 1.6 mol) in diethyl ether (700 ml).
73 mol) was added slowly to the stirred mixture to maintain the mixture at reflux. After the addition is complete, add this mixture to
The mixture was further heated for 20 minutes. Then diethyl ether (
4,4-dimethylcyclohexy-2 in 60 ml)
A solution of -en-1-one (226 g, 1.82 mol) was added dropwise over 30 minutes, the mixture was maintained at reflux and the mixture was stirred overnight. The mixture was then diluted with water (25
0 ml) and hydrochloric acid (5M, 500 ml), extracted with diethyl ether (3 x 400 ml), backwashed once with sodium bicarbonate solution (5% w/v) and once with water, then Dehydrated with anhydrous magnesium sulfate. The solvent was then flashed off and 369 g of 1-(4-
Chlorbenzyl)-4,4-dimethylcyclohexy-2
-en-1-ol was obtained as an oil. NMR (in CDCl3 solvent, tetramethylsilane as reference) Characteristic peak: δ (ppm) 0.90,
0.99 (3H, singlet), 2.78 (2H, singlet), 5.40 (1H, doublet, J=
11Hz), 5.50 (1H, doublet, J=1
1Hz), 7.17 (2H, doublet, J=8H
z), 7.26 (2H, doublet, J=8Hz)
.

(b) 1-(4-chlorobenzyl)-4,
Preparation of 4-dimethylcyclohex-1-en-3-one 1-(4-chlorobenzyl)-4,4-dimethylcyclohexy-2- obtained in step (a) in 40/60 petroleum (40 ml) En-1-ol (368g, 1.4
A solution of 7 mol) of dilute sulfuric acid (250
Sodium dichromate (217 g, 0.74 g, 2.6 mol, 98% sulfuric acid in 1.5 liters of water)
molar) solution. The reaction mixture was then diluted with 10-3
The temperature was maintained at 0° C. and stirred for 40 minutes. Water (500ml
) and diethyl ether (700ml) were added and the aqueous layer was extracted twice with diethyl ether (2 x 700ml). The organic phases were then combined and saturated sodium bicarbonate solution (1×
500 ml) and water (1 x 500 ml). The solvent was then flashed off to give 349 g of crude 1-(
4-chlorobenzyl)-4,4-dimethylcyclohex-1-en-3-one was obtained as a beige granular solid. Tritylation in petroleum gave pure samples of the desired product. Melting point 87-90°C.

Example 2 1-(4-chlorobenzyl)-1,2-epoxy-4,
Production of 4-dimethylcyclohexan-3-one (n=1
, R=4-Cl, R1=R2=CH3,
R3 = H, R6 and R7 = -O-,
R8 = H) 1726 g (6.945 mol) of crude 1-(4-chlorobenzyl)-4,4-dimethylcyclohex-1-en-3-one obtained as described in Example 1 above and A 20-liter reactor was charged with ethanol (8630 ml) and heated to 40° C. to obtain a clear pale orange solution. The reaction mixture was then cooled to 18°C,
20% (w/v) sodium hydroxide (650ml) was added slowly with cooling (ice/water) to maintain this temperature. 30% (
Aqueous hydrogen peroxide (794 ml, 7 mol) w/v) was added over 1 hour and the mixture was stirred overnight. Water (16 liters) was then added with ice cooling and the reaction mixture was stirred for 15 minutes. Centrifugation followed by water (4 x 2.
5 liters) to give an off-white solid, which was then air dried to give 1634 g of 1-(4-chlorobenzyl)-1,2-epoxy-4,4-dimethylcyclohexan-3-one. Ta. Melting point 69-70°C.

Example 3 1-(4-chlorobenzyl)-2-hydroxy-4,4
-Production of dimethylcyclohex-1-en-3-one (
n=1, R=4-Cl, R1=R2=CH
3, R3 = H, R6 and R7 = single C-C bond, R8 = OH) 38.7 g (146 mmol) obtained in Example 2 above
1-(4-chlorobenzyl)-1,2-epoxy-4
,4-dimethylcyclohexan-3-one was added to a slurry of potassium t-butoxide (33 g, 294 mmol) in t-butanol (200 ml) at 40<0>C. The mixture was then warmed to 60°C and
After stirring for an hour, the mixture was cooled with ice and the reaction was stopped with water (50 ml). 5M hydrochloric acid (100ml) was then added slowly followed by water (300ml). The mixture was then cooled to 0°C, filtered and the residue was diluted with water (10
0 ml). By drying under reduced pressure at 40°C, 36.3 g of 1-(4-chlorobenzyl)-2-
Hydroxy-4,4-dimethylcyclohex-1-en-3-one was obtained. Melting point: 80-82°C.

Example 4 Preparation of 1-(4-chlorobenzyl)-4,4,6-trimethylcyclohex-1-en-3-one (n=1,
R=4-Cl, R1=R2=R3=CH3
, R6 and R7 = single C-C bond, R
8 = H) (a) 1-(4-chlorobenzyl)-4,4
Preparation of , 6-trimethylcyclohex-2-en-1-ol A slurry of magnesium shavings (66 g, 2.73 gram atoms) in diethyl ether (300 ml) was treated with 4 chloride in diethyl ether (1500 ml).
- a solution of chlorobenzyl (418 g, 2.6 mol),
Addition was made at a rate to maintain mild reflux. 3 more
After 0 min, 4,4,6-trimethylcyclohex-2-ene-1- in diethyl ether (350 ml)
(340 g, 2.46 mol) was added and again a mild reflux was maintained. After 1 hour, the mixture was added to saturated aqueous ammonium chloride solution (4 liters) and the phases were separated. The ether phase was backwashed with water (1 liter) and used directly in the next reaction. 1-(4-chlorobenzyl)-4
, 4,6-trimethylcyclohex-2-en-1-ol was isolated and characterized (gas chromatographic analysis showed the two isomers in approximately equal amounts). NMR (in CDCl3 solvent, tetramethylsilane as reference) Characteristic peak: δ (ppm) 0.75,
0.95, 1.00, 1.02, 1.05, 1.07,
1.09 (all 9H), 2.00 (1H, multiplet), 2.57, 2.79 (2H, AB, J=1
2Hz), 2.69, 2.94 (2H, AB, J=
12Hz), 4.94 (1H, doublet, J=1
0Hz), 5.34 (1H, doublet, J=10
Hz), 7.1-7.4 (4H).

(b) 1-(4-chlorobenzyl)-4,
Preparation of 4,6-trimethylcyclohex-1-en-3-one Sodium dichromate (281 g, 0.9
A solution of 43 mol) of 1-(4-
(chlorobenzyl)-4,4,6-trimethylcyclohex-2-en-1-ol in ether. The reaction mixture was then heated to 50-60° C. over 3-4 hours, then cooled and quenched with water (2 liters) and diethyl ether (1 liter). The phases were separated and the organic phase was dissolved in 20% (w/v) sodium hydroxide (
2 x 500 ml) to give a clear light brown solution. Stripping off the solvent gave a mixture of crystalline solid and oil, which was then poured into 60/80 petroleum (1 liter).
Tritylated at 0°C, further filtered, and 315 g of 1
-(4-chlorobenzyl)-4,4,6-trimethylcyclohex-1-en-3-one was obtained as a crystalline white solid. Melting point 76-77°C.

Example 5 1-(chlorobenzyl)-1,2-epoxy-4,4,
Preparation of 6-trimethylcyclohexan-3-one (n=
1, R=4-Cl, R1=R2=R3=
CH3, R6 and R7 = -O-, R8
=H) 1-(chlorobenzyl)-4,4,6-trimethylcyclohexan-3-one (315 g, 1.2 mol) obtained in Example 4 above was mixed with methanol (1500 ml).
) and the mixture was warmed to 40° C. to give a clear yellow solution. The solution was then cooled to 10° C. and an aqueous sodium hydroxide solution (25 g in 112 ml water) was added over 10 minutes. A 30% (w/v) aqueous hydrogen peroxide solution (1
38 ml, 1.2 mol) was added over 30 minutes and the mixture was then stirred overnight. A further 30 ml was then added and the mixture was stirred for 2.5 hours. The reaction mixture was then concentrated under reduced pressure and diluted with water (2 liters) and diethyl ether (1.5 liters). The aqueous layer was then extracted with diethyl ether (2 x 0.5 liters), dried and the solvent was flashed off to give 1-(4
-chlorobenzyl)-1,2-epoxy-4,4,6-
Trimethylcyclohexan-3-one was obtained as a crystalline white solid (271 g). Melting point 58-59°C.

Example 6 1-(4-chlorobenzyl)-2-hydroxy-4,4
, 6-trimethylcyclohex-1-en-3-one (n=1, R=4-Cl, R1=R2=R
3 = CH3, R6 and R7 = single C-C
bond, R8=OH) Potassium hydroxide in flake form (30.4 g, 3 eq.) was prepared from Example 5 above in t-butanol (200 ml).
was added to the solution of 1-(4-chlorobenzyl)-1,2-epoxy-4,4,6-trimethylcyclohexan-3-one (43 g, 0.154 mol) obtained at 40 to 50 °C. , then the mixture was refluxed for 3 hours. Gas chromatography showed the presence of the desired 1-(4-chlorobenzyl)-2-hydroxy-4,4,6-trimethylcyclohex-1-en-3-one and an oil was prepared to characterize a small portion of it. isolated as.

Claims (8)

[Claims] [Claim 1] General formula: [Formula 1] [wherein n represents an integer of 0 to 5; each R is a halogen atom, nitro, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkyl Amino, dialkylamino, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl,
represents an alkylamide, cycloalkyl or phenyl group; R1, R2 and R3 independently represent a hydrogen atom or an alkyl group; R6 and R7
together represent a single carbon-carbon bond or an epoxy group; R8 represents a hydrogen atom or a hydroxyl group; however, if R6 and R7 together represent an epoxy group, R8 represents a hydrogen atom] compound. 2. The compound according to claim 1, wherein R1, R2 and R3 independently represent a hydrogen atom or a C1-4 alkyl group. 3. The compound according to claim 1 or 2, wherein R1, R2 and R3 independently represent a hydrogen atom or a methyl group. 4. Claims 1 to 3, wherein R represents a halogen atom.
A compound according to any one of. 5. n is 1, R represents a chlorine atom,
5. The compound according to claim 1, wherein R1 and R2 both represent a hydrogen atom or both represent a methyl group, and R3 represents a hydrogen atom or a methyl group. 6. (a) General formula: [In the formula, n, R, R1, R2 and R3 have the above meanings] is reacted with an oxidizing agent in the presence of an acid, R6 and R7 together represent a single carbon-carbon bond and R8 represents a hydrogen atom; (b) if desired, the compound of formula I produced in step (a); react with hydrogen peroxide in the presence of a base to form a compound of formula I in which R6 and R7 together represent an epoxy group and R8 represents a hydrogen atom; (c) if desired; , the compound of formula I produced in step (b) is converted into a compound of general formula: MOR5 in the presence of a polar solvent.
(III) [In the formula, R5 represents a hydrogen atom or an alkyl or cycloalkyl group, and M represents an alkali metal atom] to combine R6 and R7 into a single carbon-carbon indicates a bond and R8
Process for the preparation of compounds of formula I according to any of claims 1 to 5, characterized in that a compound of formula I is produced in which represents a hydroxyl group. 7. The method of claim 6, wherein the oxidizing agent in step (a) is an alkali metal dichromate. 8. The polar solvent in step (c) has the general formula: R5 OH
7. The method according to claim 6, which is a compound of (IV) in which R5 has the meaning as defined in claim 6.